WO2014189349A1 - Utilisation d'aspartate d'adénosine dans l'activation différentielle des macrophages dans des processus inflammatoires-fibrinogéniques et leur réversion - Google Patents

Utilisation d'aspartate d'adénosine dans l'activation différentielle des macrophages dans des processus inflammatoires-fibrinogéniques et leur réversion Download PDF

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Publication number
WO2014189349A1
WO2014189349A1 PCT/MX2014/000073 MX2014000073W WO2014189349A1 WO 2014189349 A1 WO2014189349 A1 WO 2014189349A1 MX 2014000073 W MX2014000073 W MX 2014000073W WO 2014189349 A1 WO2014189349 A1 WO 2014189349A1
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WIPO (PCT)
Prior art keywords
inflammatory
adenosine
macrophages
adenosine aspartate
aspartate
Prior art date
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Ceased
Application number
PCT/MX2014/000073
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English (en)
Spanish (es)
Inventor
Victoria Eugenia CHAGOYA Y HAZAS
Rebeca PÉREZ CABEZA DE VACA
Mariana DOMINGUEZ LÓPEZ
Franscisco HERNANDEZ LUIS
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Universidad Nacional Autonoma de Mexico
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Universidad Nacional Autonoma de Mexico
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Publication date
Application filed by Universidad Nacional Autonoma de Mexico filed Critical Universidad Nacional Autonoma de Mexico
Priority to CA2913233A priority Critical patent/CA2913233A1/fr
Priority to US14/893,315 priority patent/US20160120894A1/en
Publication of WO2014189349A1 publication Critical patent/WO2014189349A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis

Definitions

  • US 20120207790 Al describes an immunosuppressive agent comprising cells that proliferated by a culture of sedimented cells, obtained in turn from the centrifugation of adipose tissue to increase the macrophages M2 by transforming MI to M2 and its use for treatment scleroderma, nephritis, systemic lupus erythematosus or inflammatory pulmonary disorder.
  • an immunosuppressive agent comprising cells that proliferated by a culture of sedimented cells, obtained in turn from the centrifugation of adipose tissue to increase the macrophages M2 by transforming MI to M2 and its use for treatment scleroderma, nephritis, systemic lupus erythematosus or inflammatory pulmonary disorder.
  • the use of cell therapy in many countries has two disadvantages: the first is the lack of clinical experiences for its application in humans, and on the other hand, the design of the infrastructure for the production and maintenance of stem cells.
  • US 20120258135 describes a method for formulating an immunogenic composition for intradermal or subcutaneous administration.
  • the generation of an immune reaction may include the transformation or activation of an MI macrophage to an M2 macrophage.
  • the disadvantage is itself the immunogenic composition from bacterial or viral determinants, since said determinants are organ-specific, and the preparation and administration must be specific for each organ. as required and initially generate an infection that requires the co-administration of an anti-inflammatory to reduce it.
  • This activation of the immune response due to infection is not controlled and, if exacerbated, could cause irreversible tissue damage; the side effects are greater as with other immunogenic vaccines, there is fever and irritation at the site of administration.
  • Figures 6A and 6B refer to the results obtained regarding the distribution of macrophages.
  • Figure 6A indicates total macrophages (HIS36 + / CDllb +) in liver and
  • Figure 6B Kupffer cells inflammatory phenotype (CD163 + / CDllb / c + (MI)) evaluated by flow cytometry for 10 weeks of treatment with CC1 4 (Ci) and five and ten weeks with saline solution (SS) and IFC-305 (IFC) respectively. Percentage (%) of Kupffer cells with respect to the control ⁇ Standard error.
  • Figure 7 refers to the Western blot Arginase I. Expression of the protein in total liver homogenate in the different experimental groups treated with IFC-305 and saline solution for five and ten weeks.
  • the present invention relates to the use of adenosine aspartate, referred to herein as IFC-305, in the differential activation of macrophages in inflammatory-fibrogenic processes and their reversal.
  • adenosine aspartate is a farmochemical compound that presents itself the ability to induce gamma PPAR.
  • the authors of the present invention have found that adenosine aspartate is an inducer of the M2 phenotype macrophage and therefore represents a pharmacological option for inflammatory-fibrogenic diseases.
  • the MI reaction is induced with pathogens and the change to M2 by the addition of 11-4 and IL-13;
  • the M1-M2 interconversion through endogenous adenosine is then discussed as an alternative mechanism independent of IL-4 / IL-13.
  • the present invention describes the decrease in MI macrophages and achieves the conversion to M2 by exogenous adenosine aspartate administered in high concentrations (in relation to cells), without this involving secondary reactions and / or toxicity to the organism; actually the Adenosine aspartate has a longer life than adenosine and is effective at a lower dose (in relation to a dose administered to humans) compared to said compound.
  • the immunomodulatory effect of adenosine is mainly mediated by adenosine receptors (Al, A2a, A2b and A3), salts derived from adenosine can then interact with the receptors thanks to metabolism of the molecule or cellular energy balance by modulating the differential activation of macrophages and the immune response.
  • adenosine receptors Al, A2a, A2b and A3
  • salts derived from adenosine can then interact with the receptors thanks to metabolism of the molecule or cellular energy balance by modulating the differential activation of macrophages and the immune response.
  • adenosine salt has the ability to react in any organ since practically all human cells possess adenosine receptors or transporters, whereby administration can be performed by any route without representing a risk of immunological hyperreactivation.
  • adenosine aspartate may be contained in a pharmaceutical composition, which must contain a therapeutically effective amount of adenosine aspartate in combination with one or more pharmaceutically acceptable excipients.
  • adenosine aspartate has a longer life than endogenous adenosine, it is effective at a lower dose.
  • Figures 1A to 1C clearly show the increase in pro-inflammatory cytokines (IL-i- Figure 1A, IL-4- Figure IB and IL-6- Figure 1C) at 4, 6 and 8 weeks of induction of cirrhosis with CC1 4 and decreased same in the presence of adenosine aspartate; except in IL-6 at 8 weeks of treatment, showing the anti-inflammatory effect of the compound.
  • the serum results indicate a decrease in the pro-inflammatory cytokines IL- ⁇ , IL-4 showing a clear anti-inflammatory effect.
  • liver homogenate the same effect is observed at 8 weeks.
  • the dual effect of IL-6 is observed by a decrease at 6 weeks and an increase in serum and liver at 8 weeks, indicating changes in the secretion pattern of proinflammatory and profibrogenic molecules by the administration of the compound, protecting the liver of an inflammatory and fibrogenic process.
  • cirrhosis Once cirrhosis is established, the animals are divided into five groups: group I, treatment with CC14 is suspended, cirrhosis control animals are sacrificed, groups II and III allow cirrhosis to progress and receive three ip injections of saline per week for 5 and 10 weeks, groups IV and V receive three injections of the compound at a dose of 50 mg / kg ip for 5 and 10 weeks; at the time of sacrifice, serum and liver samples are taken.
  • Figure 5 refers to a graph showing the total number of Kupffer cells quantified with CDl63 + / CDllb / c + during 4, 6, 8 and 10 weeks of treatment with ICC 4 , showing an increase during the development of cirrhosis that decreases with the treatment of compound IFC-305.
  • Figure 6 refers to the results of liver homogenate in relation to macrophage distribution.
  • Figure 6A refers to the total macrophages using the HIS36 + ⁇ / CDllb + marker, where a significant decrease in cirrhosis and increase during cirrhosis progression and with the treatment of IFC-305 was observed.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne l'utilisation d'aspartate d'adénosine pour l'activation différentielle des macrophages dans des processus inflammatoires-fibrinogéniques et leur réversion.
PCT/MX2014/000073 2013-05-22 2014-05-20 Utilisation d'aspartate d'adénosine dans l'activation différentielle des macrophages dans des processus inflammatoires-fibrinogéniques et leur réversion Ceased WO2014189349A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CA2913233A CA2913233A1 (fr) 2013-05-22 2014-05-20 Utilisation d'aspartate d'adenosine dans l'activation differentielle des macrophages dans des processus inflammatoires-fibrinogeniques et leur reversion
US14/893,315 US20160120894A1 (en) 2013-05-22 2014-05-20 Use of adenosine aspartate in the differential activation of macrophages in inflammatory-fibrogenic processes and its reversal

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
MXMX/A/2013/005735 2013-05-22
MX2013005735A MX2013005735A (es) 2013-05-22 2013-05-22 Uso de aspartato de adenosina en la activacion diferencial de los macrofagos en procesos inflamatorios-fibrogenicos y su reversion.

Publications (1)

Publication Number Publication Date
WO2014189349A1 true WO2014189349A1 (fr) 2014-11-27

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/MX2014/000073 Ceased WO2014189349A1 (fr) 2013-05-22 2014-05-20 Utilisation d'aspartate d'adénosine dans l'activation différentielle des macrophages dans des processus inflammatoires-fibrinogéniques et leur réversion

Country Status (4)

Country Link
US (1) US20160120894A1 (fr)
CA (1) CA2913233A1 (fr)
MX (1) MX2013005735A (fr)
WO (1) WO2014189349A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2186519A1 (fr) * 2007-09-06 2010-05-19 Universidad Nacional Autonoma De Mexico Utilisation de l'aspartate d'adénosine pour la préparation de produits pharmaceutiques destinés au traitement du cancer du foie
WO2012149557A1 (fr) * 2011-04-28 2012-11-01 New York University Inhibiteurs de mir-33 et utilisations de ceux-ci pour diminuer une inflammation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2186519A1 (fr) * 2007-09-06 2010-05-19 Universidad Nacional Autonoma De Mexico Utilisation de l'aspartate d'adénosine pour la préparation de produits pharmaceutiques destinés au traitement du cancer du foie
WO2012149557A1 (fr) * 2011-04-28 2012-11-01 New York University Inhibiteurs de mir-33 et utilisations de ceux-ci pour diminuer une inflammation

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HERNANDEZ-MUNOZ R 1131: "Effectiveness of aspartate of adenosine as hepatoprotective and anti-fibrotic agent as compared with the parental adenosine", HEPATOLOGY (AASLD ABSTRACTS), vol. 38, USA, pages 700 - 701, XP004624342, DOI: doi:10.1016/S0270-9139(03)81169-2 *
PEREZ-CARREON J I ET AL.: "An adenosine derivative compound, IFC305, reverses fibrosis and alters gene expression in a pre-established CC14-induced rat cirrhosis", INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY, vol. 42, no. 2, GB, pages 287 - 296, XP026853885 *

Also Published As

Publication number Publication date
MX2013005735A (es) 2014-11-24
US20160120894A1 (en) 2016-05-05
CA2913233A1 (fr) 2014-11-27

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